Efficient Synthesis of Spirooxindole Pyrrolones by a Rhodium(III)‐Catalyzed C−H Activation/Carbene Insertion/Lossen Rearrangement Sequence

Abstract

Ar hodium(III)-catalyzed domino annulation of simple olefins with diazo oxindoles to give spirooxindole pyrrolone products is described. This reaction can be formally viewed as the result of an anomalous tandem CÀHactivation, carbene insertion, Lossen rearrangement, and an ucleophilic addition process.T he potential utility of this reaction was further demonstrated by the late-stage diversification of drug molecules.Spirooxindole frameworks can be found in al arge number of natural or synthetic compounds with potent bioactivity profiles. [1] Thei ntroduction of spiro-containing systems not only influences the biological activity and physicochemical property of the parent compounds in drug discovery programs,but also increases structural novelty for patentability. [2] Nowadays,c ommon methods for the synthesis of spirooxindoles include [3+ +2] cycloadditions, [3] Mannich reactions, [4] rearrangements of strained rings, [5] and nucleophilic substitution. [6] However,many of these existing methods suffer from certain limitations,s uch as complicated starting materials, multistep strategies,n arrow substrate scopes,o rh arsh reaction conditions.G reat attention is still devoted to the development of novel and simple methods for the synthesis of such compounds.As C À Ha ctivation has shown great potential in the generation of complex skeletons in as imple and atomeconomic fashion from readily available precursors, [7] the development of an elegant one-step C(sp 2 )ÀHf unctionalization reaction for the construction of spirooxindoles has attracted the attention of synthetic chemists.Aseries of palladium-catalyzed spirocyclizations involving sequential carbopalladation, intramolecular C À Ha ctivation, and electrophile insertion have been achieved. [8] Alternatively,aRh IIIcatalyzed annulation of N-pivaloyloxy benzamides with diazo compounds to provide isoindolones has also been reported [9] (Scheme 1A). Like the CÀHa ctivation of arenes,a lkene CÀHa ctivation has also received significant attention in recent years. [10] Moreover,m ultisubstituted spirooxindole pyrrolones could be synthesized by C À Ha ctivation of simple olefins.H erein, we described aR h III -catalyzed domino annulation of N-pivaloyloxy acrylamides with diazo oxindoles to give spirooxindole pyrrolone products in good yields and with excellent regioselectivities (Scheme 1B). This reaction could proceed through aC ÀHa ctivation, carbene insertion, Lossen rearrangement, and nucleophilic addition sequence.T he potential utility of this method in late-stage diversification for drug discovery was exemplified by the direct introduction of spirooxindole pyrrolone skeletons into the drug compounds pentoxifylline,e ndofolliculina, and pregnenolone.Fort he construction of the spirooxindole pyrrolone architecture,w eb egan our investigation by choosing N-pivaloyloxy methacrylamide 1a and diazooxindole 2a as the substrates.Inthe presence of 2.5 mol %[RhCp*Cl 2 ] 2 and 0.2 equiv of Cs 2 CO 3 in MeCN,the expected compound 3 was not formed. However,t he rearranged ...

An unusual four-step cascade reaction for accessing furo[3,4-c]pyridine-1,4-dionesviarhodium catalysis

“…By taking advantage of the strategy of directing group rearrangement, a series of intriguing spirooxindole pyrrolones were synthesized elegantly by Dai's group (Scheme 1b). 6 Acrylamides involving the rearrangement of DGs undergo three processes: C-H activation, directing group rearrangement, and annulation. Recently, we developed an efficient rhodium-catalyzed domino C-H alkenylation, DG migration, and lactonization reaction between N-carbamoyl indoles and 4-hydroxy-2-alkynoates for the synthesis of the furan-2(5H)-one scaffold (Scheme 1c).…”